dinoprost and Mastocytosis

Mast cells leave evidence, a "fingerprint," of their participation in acute and chronic clinical events. That fingerprint is an elevation, either chronic or acute, in levels of their secreted mediators or their metabolites. Of these, only serum tryptase is currently one of the diagnostic criteria for systemic mastocytosis or mast cell activation. Combinations of easily obtained and quantified urinary mast cell mediator metabolite levels correlate well with bone marrow findings of systemic mastocytosis. By inhibiting synthesis of or blockading receptors to the elevated mast cell mediator, relief of clinical symptoms can often be achieved.

Topics: Biomarkers; Cell Degranulation; Dinoprost; Histamine; Humans; Inflammation Mediators; Leukotriene E4; Mast Cells; Mastocytosis; Neuropeptides; Practice Guidelines as Topic; Tryptases

Although 4 mast cell mediators can be routinely measured, the results of initial testing to evaluate symptoms of mast cell activation have not been widely reported.. We examined the results of mast cell mediator tests used to assess patients with mast cell activation symptoms during a 5-year time span.. After excluding patients with alternative diagnoses, records of 108 patients were reviewed for initial mediator test results. Mediators included serum tryptase plus urinary N-methyl histamine (N-MH), leukotriene (LT)E4, and 11β-prostaglandin (PG) F2α or 2,3-dinor-11β-PGF2α (BPG).. Most commonly, either a single measured elevation of 1 mediator (48.1%) or elevations of 2 (33.3%) mediators was found at baseline, during symptoms or at both time points. Elevated levels of a single mediator in order of frequency were: BPG > tryptase > LTE4 > N-MH, and for two mediators: BPG + tryptase (n = 16 cases) > BPG + LTE4 (n = 9) > BPG + N-MH (n = 6). Elevations in 3 mediators (n = 8) or 4 mediators (n = 2) were much less frequent. Monoclonal mast cell activation syndrome (n = 6), and systemic and cutaneous mastocytosis (n = 4) were also infrequent. Baseline plus symptom-associated tryptase values were obtained in only 7 patients.. This survey suggests that elevations of 1 or 2 mediators are the most common (total 81.4% of cases) findings from initial tests for mast cell activation. Elevated levels of BPG were most commonly found both singly and in combination with other mediators, followed by the finding of elevated levels of tryptase. Baseline plus symptom-associated tryptase levels were measured in only a minority of patients.

Topics: Dinoprost; Flushing; Humans; Leukotriene E4; Mast Cells; Mastocytosis; Methylhistamines; Surveys and Questionnaires; Tryptases

Topics: Abdominal Pain; Adult; Anaphylaxis; Angioedema; Anti-Asthmatic Agents; Biomarkers; Cromolyn Sodium; Diarrhea; Dinoprost; Female; Histamine Antagonists; Humans; Leukotriene E4; Male; Mast Cells; Mastocytosis; Middle Aged; Omalizumab; Prostaglandin D2; Treatment Outcome; Tryptases; Urticaria

The utility of measuring histamine and prostaglandin metabolites in the urine of patients with mastocytosis has not been critically examined in a large series of patients. This study examined the relationship between the extent of increase in urinary excretion of 11β-prostaglandinF2α and N-methyl histamine, with serum tryptase, whole blood serotonin, and bone marrow findings including morphology, percentage involvement, and abnormal mast cell phenotype.. This was a retrospective analysis of 90 patients who were continuously enrolled in the study for a period of 6 years (2008-2014). We recorded serum tryptase, whole blood serotonin, levels of urinary mast cell metabolites 11β-prostaglandinF2α and N-methyl histamine (NMH), and bone marrow findings.. Urinary mast cell metabolites 11β-prostaglandinF2α and N-methyl histamine correlated with levels of serum tryptase, mast cell burden in the bone marrow, the presence of mast cell aggregates, and atypical mast cells on bone marrow biopsy. Whole blood serotonin did not have a significant correlation with the serum tryptase or mast cell burden in the bone marrow. Urinary NMH was significantly different between c-kit D816V-positive and c-kit D816V-negative patients, while 11β-prostaglandinF2α was not. Urinary 11β-prostaglandinF2α 24-h excretion >3500 ng and NMH levels >400 μg/gm Cr corresponded with the high degree of bone marrow biopsies positive for atypical mast cells, the presence of aggregates, and c-kit mutation.. Easily obtained and quantified urinary metabolites of histamine (greater than twice the upper limit of normal) and prostaglandin D2 (>3.4 times the upper limit of normal) correlate well with bone marrow findings of mastocytosis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Biopsy; Bone Marrow; Child; Dinoprost; Female; Humans; Male; Mast Cells; Mastocytosis; Methylhistamines; Middle Aged; Mutation; Proto-Oncogene Proteins c-kit; Retrospective Studies; Serotonin; Tryptases; Young Adult

The symptoms and hemodynamic alterations that accompany episodes of systemic mast cell activation have been largely attributed to excessive prostaglandin (PG)D2 release. Quantification of the major urinary metabolite of PGD2 has been invaluable in elucidating a role for PGD2 in these clinical entities and in the biochemical evaluation of systemic mastocytosis. With the use of a modified mass spectrometric assay for the major urinary metabolite of PGD2, this metabolite was detected in plasma from 10 normal volunteers (3.5 +/- 1.4 pg/ml). Ingestion of niacin, which induces endogenous release of PGD2, increased plasma levels of this metabolite 6.3 to 33 times above the upper limit of normal by 2 hours. Thereafter, levels declined gradually but remained elevated for up to 6 to 8 hours. In contrast, circulating levels of 9 alpha, 11 beta-PGF2, the initial metabolite of PGD2, peaked by 30 minutes and returned to baseline by 2 hours. The clinical utility of measuring the major urinary metabolite in the circulation was demonstrated by detection of markedly increased levels in plasma and serum from patients with systemic mastocytosis and a patient with a severe type I allergic reaction. Thus in the biochemical evaluation of episodes of systemic mast cell activation and endeavors to further elucidate the role of PGD2 in human disease, there are kinetic advantages of measuring the major urinary metabolite of PGD2 in the circulation. One particular advantage is the evaluation of clinical events, which only in retrospect are suspected to be associated with excessive release of PGD2, yet plasma or serum was obtained proximate to the event.

Topics: Anaphylaxis; Dinoprost; Drug Stability; Drug Storage; Female; Humans; Kinetics; Male; Mastocytosis; Niacin; Prostaglandin D2; Prostaglandins D; Time Factors; Urticaria Pigmentosa

Prostaglandin (PG) D2 has been shown to be transformed by human 11-ketoreductase to 9 alpha,11 beta-PGF2, a biologically active metabolite that is produced in vivo. During the course of developing a mass spectrometric assay for 9 alpha,11 beta-PGF2, several compounds with characteristics similar to PGF2 were detected in both plasma and urine of normal humans by selected ion monitoring. Analysis of pooled plasma obtained from patients with mastocytosis during severe episodes of systemic mast cell activation associated with the release of markedly increased quantities of PGD2 was revealing in that all of these compounds were present in approximately 800-fold greater abundance compared to levels found in normal plasma, suggesting that these compounds arose from PGD2 metabolism. Complete electron impact mass spectra were obtained of these compounds in both plasma and urine; these spectra established that they were all isometric forms of PGF2. Approximately 16 isomeric PGF2 compounds were identified. Treatment with butylboronic acid indicated that the C-9 and C-11 hydroxyls were trans in approximately one-third of the compounds and cis in approximately two-thirds. Preliminary experiments suggest that PGD2 is a very labile compound in vivo and undergoes extensive isomerization, after which reduction by 11-ketoreductase yields a family of more stable isomeric PGF2 compounds. Elucidating the profile of biological activity of these compounds and their mechanism of formation will contribute importantly to our understanding of the biological consequences of PGD2 release in vivo. These results also bring into question the reliability of assays for PGF2 alpha and its metabolites in human biological fluids as a specific index of endogenous PGF2 alpha biosynthesis, as these assays may also measure in part isomeric PGF2 compounds arising from PGD2 metabolism.

Topics: Dinoprost; Gas Chromatography-Mass Spectrometry; Humans; Isomerism; Mass Spectrometry; Mastocytosis; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Reference Values

Topics: Dinoprost; Humans; Mast Cells; Mastocytosis; Prostaglandin D2; Prostaglandins D; Prostaglandins F; Stereoisomerism